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Abstract

Persistent Organic Pollutants (POPs) are highly stable chemicals that are widespread in nature with potential hazardous effects in humans and wildlife. POPs have been used in a multitude of industrial applications and household products over several decades. Due to persistent, bioaccumulative and toxic (PBT) properties, regulations have been imposed for compounds like perfluorinated alkylated substances (PFASs), brominated flame retardants (BFRs) and polychlorinated biphenyls (PCBs). Because of high resistance against degradation, they are still present at considerable amounts in the environment, even after widespread bans. The deleterious effects of some POPs upon human health are well documented. They are known to cause cancer, immunotoxicity, neurotoxicity and interfere with reproduction and development. Concerns have been raised about the impact of POPs upon neuronal development and possibly neurodevelopmental disorders. Children are thought to be especially at risk due to the immature blood-brain barrier (BBB) and the highly dynamic, complex events of neuronal development occurring early in life. However, very few studies have previously been reported on the effects of POPs in mixture, and on neurodevelopmental mechanisms using in vitro test models at human relevant exposures. Aiming to close this knowledge gap, our studies were conducted on PC12 cells and Neuronal Stem Cells (NSCs) derived from human induced pluripotent stem cells (HiPSC) using concentrations of POPs comparable to human blood levels. Four different mixtures of 29 perfluorinated, brominated, and chlorinated substances were used. Cells were examined using cell viability methods, immunological techniques with high-content imaging (HCI), and qPCR, probing for changes in neurodevelopmental endpoints connected to molecular initiating events (MIE) and key events (KEs) of the adverse outcome pathway (AOP) framework. The present study showed that exposure to mixtures of POPs induced decreased cell viability in PC12 cells. In contrast to this, relevant concentrations of the POPs induced a concentration-dependent increase in cell viability in the NSCs. Mechanistic studies revealed increases in key neurodevelopmental proteins (SYP, PSD95, MAP2, and BDNF) at exposures below human blood level average. This was, however not reflected in gene expression. Our results indicate that exposure to POPs during early neurodevelopment may lead to detrimental perturbation of essential MIE or KEs important for learning and memory and the developing brain of children.